Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we investigated the effect of the novel retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN/CD437) on the growth of human lung carcinoma cell lines. AHPN inhibits the proliferation of all cell lines tested, irrespective of the lung tumor type, in a concentration- and time-dependent manner. A dramatic reduction in cell number was observed in adenocarcinoma H460 cells, and was shown to be related to an induction of apoptosis. Bromodeoxyuridine (BrdU) incorporation and flow-cytometric analyses indicated that treatment of H460 cells with AHPN induces cell-cycle arrest at the G1 phase. We therefore investigated the effect of AHPN on several regulatory proteins of the G1 phase of the cell-cycle. The cell-cycle arrest induced by AHPN was accompanied by an inhibition of the hyperphosphorylation of the retinoblastoma (Rb) protein, an indication of G1 arrest. Furthermore, two cyclin-dependent kinases, cdk2 and cdk4, which are normally involved in the phosphorylation of Rb, were shown to have decreased activity. In some cell lines, the decrease in cdk activity may be partly related to an increase in p21(WAF1/Cip1) (p21), an inhibitor of cyclin-dependent kinases. No changes were observed in the cyclin-dependent kinase inhibitor p27(Kip1). The observed increase in p53 in response to AHPN could at least to some extent be responsible for the increased levels of p21. The increase in p53 expression was found to be regulated at a post-transcriptional level. Our results suggest that the growth inhibition of certain lung carcinoma cell lines by AHPN is at least partly related to an increase in p21. However, in other cell lines, different mechanisms appear to be involved. The specificity with which AHPN and other retinoids induce growth arrest and p21 expression indicates that the action of AHPN is not mediated by RAR or RXR receptors, but involves a novel signaling pathway.
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PMID:Inhibition of cell proliferation and induction of apoptosis by the retinoid AHPN in human lung carcinoma cells. 949 Jun 50

A novel synthetic retinoid, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), is a selective ligand of the RARgamma nuclear receptor. We examined the in vitro effects of CD437 and found that CD437 induces S phase arrest within 24 to 48 h, followed by cell death, in the p53-negative Hep3B and the p53-positive HepG2 human hepatoma cell lines. Based on observations of cellular and nuclear fragmentation, chromatin condensation, and DNA fragmentation, the CD437-mediated cell-killing effect appears to be due to apoptosis. On morphological examination, a number of CD437-treated cells were found to have increased 5- to 10-fold in size and persisted as single giant cells without cell division, while the remainder underwent nuclear division (multiple nuclei) but were unable to complete cytokinesis, and finally all died by apoptosis. In HepG2 cells that possessed wild-type p53, CD437-induced S phase arrest and apoptosis were accompanied by the up-regulation of cyclin A, cyclin B, p53, p21(CIP1/Waf1), Bad, and Bcl-Xs proteins and by a decrease in Bcl-2 protein levels. In Hep3B cells, CD437-mediated S phase arrest and apoptosis were also associated with a concomitant up-regulation of cyclin A, cyclin B, Bad, and Bcl-Xs. However, Hep3B cells did not express p53 or Bcl-2 messages. Olomoucine and roscovitine, the potent p34(cdc2) and CDK2 inhibitors, effectively blocked CD437-mediated cyclin A- and B-dependent kinase activation and prevented CD437-induced cell death. Furthermore, antisense oligonucleotide complementary to cyclin A and B mRNA significantly rescued CD437-induced apoptosis. These findings suggest that activation of cyclin A- and B-dependent kinases is a critical determinant of apoptotic death mediated by CD437.
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PMID:Involvement of cyclin-dependent kinase activities in CD437-induced apoptosis. 1052 23

The addition of all-trans-retinoic acid has been found to mediate a G1 cell cycle phase arrest but not apoptosis in normal mammary epithelial cells. We have now found that addition of the novel retinoid 6-[3-(1-adamantyl)]-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), which appears to function through a pathway independent of retinoic acid nuclear receptors, results in an S-phase arrest that is preceded by a 4-fold elevation in the levels of the cyclin-cyclin dependent kinase (cdk) inhibitor p21WAF1/CIP1. Failure to inhibit E2F-1 activation of genes through its phosphorylation by the cyclin cdk2 kinase has been shown to result in S-phase arrest and apoptosis in a number of cell types. Although exposure of the normal mammary cells to CD437 does not result in modulation of cyclin A or cdk2 levels, an increase in E2F-1 levels and a marked inhibition of cyclin A/cdk2 kinase activity are observed. Exposure to CD437 results in enhanced E2F-1 binding to its DNA consensus sequences and transcriptional activity during S phase. We hypothesize that this enhanced E2F-1 transcriptional activity results in S-phase arrest and subsequent apoptosis that has been observed in other systems.
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PMID:S-phase arrest and apoptosis induced in normal mammary epithelial cells by a novel retinoid. 1076 94

The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) induces growth arrest and apoptosis in various tumor cell lines including non-small cell lung cancer (NSCLC) cells. CD437 binds retinoic acid receptor gamma (RARgamma) selectively, and can enhance receptor-dependent transcriptional activation of various genes. However, some of the effects of this retinoid on cell growth inhibition and apoptosis appear to be receptor-independent. To gain a better understanding of the mechanism by which CD437 exerts its effects, we employed a high throughput western blotting method (PowerBlottrade mark) using 760 monoclonal antibodies to compare the levels of their target cellular signaling proteins in untreated and CD437-treated NSCLC H460 cells. CD437 (1 microM, 24 h) increased the levels of 70 proteins and decreased the levels of 28 proteins. These proteins play a role in fundamental cellular processes including: DNA synthesis and repair, transcription and DNA-binding, cell cycle, apoptosis, cytoskeleton assembly, cell adhesion, endocytosis, growth and signal transduction. Some proteins identified by this approach have been implicated previously in the effect of CD437 (e.g., p53, Bax, cyclin B, CDK2). Additionally we identified proteins that are novel candidates for mediating the cellular responses to CD437 (e.g., FAF1, Bid, caspase 8, cdk1, KAP, NDR, RBBP, 53BP2, Grb2, PLCgamma1, p70s6k, PP2Cdelta, PKBalpha/AKT, PDK1, and several DNA repair enzymes).
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PMID:Identification of protein modulation by the synthetic retinoid CD437 in lung carcinoma cells using high throughput immunoblotting. 1564 34

In the preset study we measured the concentrations of 16 priority PAHs in maternal blood and placental tissue by using the GC-MS/MS system, and investigated the effects of selected PAHs (naphthalene, anthracene, phenanthrene, pyrene) and mixtures on BeWo and JEG-3 human placental cell line proliferation (Alamar Blue), cytotoxicity (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (XTT), lactate dehydrogenase (LDH), acid phosphatase (AP), endocrine activity (progesterone and estradiol secretion) and apoptosis (cyclin A1, cyclin D2, cdk 2, cdk 4, Bcl-xl, Bax, and caspase-3 protein expression). The concentrations of 16 PAHs in maternal blood were higher than in placental tissue. In JEG-3 cells except for naphthalene, all PAHs studied and their mixtures at maternal doses, and only naphthalene at placental doses, increased XTT, while in BeWo cells, placental doses increased XTT and AP activity. A cell-type dependent action: a proapoptotic effect (increased Bax and caspase-3) in BeWo cells and an antiapoptotic effect (decreased Bax and increased cdk2 and cyclin D1) in JEG-3 cells was observed. Naphthalene, pyrene, and phenanthrene exhibited an endocrine-disrupting effect in JEG3 cells but not in BeWo cells. Our results provide evidence of cell specific effects of selected low molecular weight PAHs on proliferation, the cell cycle, proapoptotic protein expression, and hormone secretion.
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PMID:Cell-specific and dose-dependent effects of PAHs on proliferation, cell cycle, and apoptosis protein expression and hormone secretion by placental cell lines. 2880 81